Highlights
- •We evaluated the effect of p38MAPK inhibitor, BMS-582949, on arterial inflammation.
- •Subjects with known ASCVD were randomized to BMS-582949, placebo, or atorvastatin.
- •We demonstrate that treatment with BMS-582949 did not reduce arterial inflammation.
- •Intensification of statin therapy (positive control) reduced arterial inflammation.
Abstract
Objectives
This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK)
inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using 18FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis
and its inhibition may lead to reduced inflammation within atherosclerotic plaques.
Methods
Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy
and having at least one lesion with active atherosclerotic plaque inflammation in
either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily),
placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was
assessed using 18FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial 18FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of
the index vessel, and 2) within active slices of all vessels (AS: which includes only
slices with significant inflammation (TBR ≥ 1.6) at the baseline).
Results
Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo,
(ΔTBR index: 0.10 [95% CI: −0.11, 0.30], p = 0.34; ΔTBR AS: −0.01 [−0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs.
16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification
was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: −17.44% [54.68]
vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = −0.24 [95% CI: −0.46, −0.01], p = 0.04).
Conclusions
The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of
treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared
to placebo, whereas intensification of statin therapy significantly decreased arterial
inflammation.
Keywords
Abbreviations:
18FDG (18F-fluorodeoxyglucose), hs-CRP (high sensitivity C-reactive peptide), MAPK (mitogen-activated protein kinase), PET (positron emission tomography), ROI (region of interest), SUV (standardized uptake value), TBR (target-to-background ratio)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: March 28, 2015
Accepted:
March 25,
2015
Received in revised form:
March 16,
2015
Received:
November 26,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
